Chemotherapy principles in the treatment of prostatic cancer

Könyves, I.; Müntzing, Jonas; Rozencweig, Marcel

doi:10.1002/pros.2990050106

Cited by 13 publications

(7 citation statements)

References 27 publications

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“…The effect of combining hormonal treatment consisting of agonist [D-Lys6]LH-RH with various chemotherapeutic agents was investigated in the Dunning R-3327H rat prostate cancer model [19,20]. The combination of cyclophosphamide (Cytoxan) or mitoxantrone (Novantrone) with [D-Lys6]LH-RH led to a better inhibition of prostate cancer than [D-Lys6]LH-RH alone, and seemed to arrest tumor growth [ 19,201. These results suggest that combined administration of LH-RH agonists with chemotherapeutic agents might inhibit the proliferation of androgen-dependent as well as independent cells and improve therapeutic response [ 19,201. A modern class of drugs developed for the therapy of prostate cancers was based on cytotoxic estrogens, nitrogen mustard compounds chemically coupled to carrier estrogens for enhancing selectivity and specificity [32,33]. These compounds, like estracyte (estramustine), accumulate in the rat prostate due to the presence in the ventral lobe of the prostate of a protein (EMBP) that binds estramustine with high affinity and high capacity [32,33].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of growth of experimental prostate cancer in rats by LH‐RH analogs linked to cytotoxic radicals

Pinski¹,

Yano

Szepesházi

et al. 1993

The Prostate

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The effects of hybrid cytotoxic LH-RH analogs, produced by linking anthraquinone or methotrexate to carrier LH-RH agonist [D-Lys6]LH-RH, were evaluated in Copenhagen-Fisher F1 rats bearing Dunning R-3327H prostate adenocarcinoma. The two cytotoxic LH-RH analogs T-98 [(D-Lys6)LH-RH coupled to glutaryl-2-(hydroxymethyl)anthraquinone (G-HMAQ)], and AJ-04 [(D-Lys6)LH-RH linked to methotrexate (MTX)], carrier [D-Lys6]LH-RH, or the free cytotoxic compounds MTX and G-HMAQ were administered from Alzet Osmotic minipumps for 7-8 weeks. The cytotoxic LH-RH analogs caused somewhat greater tumor growth inhibition than the carrier peptide, while anthraquinone or methotrexate alone, administered in equimolar doses, were ineffective. The inhibition of androgen sensitive organs (testes, ventral prostates, and seminal vesicles) was pronounced with both carrier and cytotoxic analogs, showing the latter to be fully hormonally active in suppressing the pituitary-gonadal axis. Histological changes were also evaluated. The inhibition of mitosis and the frequency of apoptosis were higher in tumors treated with AJ-04, T-98, [D-Lys6]LH-RH, or by castration than in those of controls. Serum hormone levels were lowered by both carrier peptide and cytotoxic analogs, LH being substantially depressed, and testosterone not detectable. These results and other findings indicate that LH-RH analogs containing cytotoxic radicals anthraquinone or methotrexate retain their hormonal activity after administration in vivo, and can effectively inhibit tumor growth. Extensive further studies are required on this new class of compounds, but apparent binding of cytotoxic LH-RH analogs to tumors such as prostate cancer, which have receptors for LH-RH, could greatly reduce peripheral toxicity of chemotherapeutic agents. This approach, based on targeted chemotherapy, might be of practical therapeutic importance for the management of advanced prostate cancers, which eventually relapse after palliative hormonal therapy.

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Section: Discussionmentioning

confidence: 99%

Inhibition of growth of experimental prostate cancer in rats by LH‐RH analogs linked to cytotoxic radicals

Pinski¹,

Yano

Szepesházi

et al. 1993

The Prostate

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“…The use of both approaches, endocrine and chemotherapeutic, may increase the rate of response and its duration. The response rates in advanced prostatic carcinoma that may be achieved at present with chemotherapy alone are generally low, and complete regressions are rare (30). Over the past decade many chemotherapeutic agents have been tested, alone or in combination, in patients with hormonally unresponsive prostate carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Combination of long-acting microcapsules of the D-tryptophan-6 analog of luteinizing hormone-releasing hormone with chemotherapy: investigation in the rat prostate cancer model.

Schally¹,

Redding²

1985

Proc. Natl. Acad. Sci. U.S.A.

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The effect of combining hormonal treatment consisting of long-acting microcapsules of the agonist [D-Trp6]LH-RH (the D-tryptophan-6 analog of luteinizing hormone-releasing hormone) with the chemotherapeutic agent cyclophosphamide was investigated in the Dunning R-3327H rat prostate cancer model. Microcapsules of LH-RH formulated from poly(DL-lactide-co-glycolide) and calculated to release a controlled dose of 25 pg/day were injected intramuscularly once a month. Cyclophosphamide (Cytoxan) (5 mg/kg of body weight) was injected intraperitoneally twice a week.When the therapy was started 90 days after tumor transplantation-at the time that the cancers were well developed-and was continued for 2 months, tumor volume was significantly reduced by the microcapsules or Cytoxan given alone. The combination of these two agents similarly inhibited tumor growth but did not show a synergistic effect. In another study, the treatment was started 2 months after transplantation, when the developing tumors measured 60-70 mm3. (1,19,20), but hormone-independent cells originally present in the tumor, by a clonal selection process, eventually repopulate the tumor. As the prostate cancer progresses to a hormone-independent state, this produces a relapse to androgen-ablation therapy (1,19,20). The histological and biochemical similarities of the Dunning R-3327H prostate tumor to human prostate adenocarcinoma have made this tumor an acceptable model for the study of human prostate cancer. From 70% to 90%o of the cells of this tumor appear to be dependent on androgen for maximal growth stimulation (1,19). Rats bearing this tumor respond for a long period of time to surgical castration by tumor involution. However, after this initial response to castration, the tumor relapses and growth is reinitiated (1). Thus, this tumor was chosen since it mimics many of the properties of human prostate carcinoma.Antineoplastic agents have the established ability to kill tumor cells (1,(18)(19)(20)(21)(22)(23). Cyclophosphamide (Cytoxan) is one of the most commonly used agents for chemotherapy of prostate carcinoma and has had the most extensive trials (21-23). It is possible that the use of a combination of chemotherapeutic and hormonal methods would prevent or delay a condition whereby hormone-insensitive cells present in the originally endocrine-dependent tumor subsequently become the predominant component (1,18,19,22,23 tSchally,

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“…The first hormonally targeted chemotherapeutic agents developed for the treatment of prostate cancer and breast cancer used estrogenic steroid molecules as carriers for various alkylating agents (13,14). Nitrogen mustard compounds were chemically coupled to carrier estrogens for enhancing selectivity and cytotoxicity on estrogen receptor-positive cells (13,14).…”

Section: Hormonal Chemotherapeutic Agentsmentioning

confidence: 99%

“…Nitrogen mustard compounds were chemically coupled to carrier estrogens for enhancing selectivity and cytotoxicity on estrogen receptor-positive cells (13,14). The cytotoxic estrogens, such as estracyte (estramustine), accumulate in the rat prostate due to the presence in the ventral lobe of the prostate of a protein that binds estramustine with high affinity and high capacity (13,14).…”

Section: Hormonal Chemotherapeutic Agentsmentioning

confidence: 99%

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Schally

Nagy²

1999

European Journal of Endocrinology

266

228

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In view of non-specific toxicity of most chemotherapeutic agents against normal cells, the development of targeted chemotherapy is warranted. Efficient targeting of chemotherapeutic drugs to the cancerous area could be of great benefit for patients with advanced or metastatic tumors. Targeted cytotoxic peptide conjugates are hybrid molecules composed of a peptide carrier which binds to receptors on tumors and a cytotoxic moiety. New cytotoxic analogs of LHRH, AN-152 in which doxorubicin (DOX) is linked to ]LHRH, and AN-207 which consists of 2-pyrrolino-DOX (AN-201) coupled to the same carrier, show high-affinity binding and are much less toxic and more effective in vivo than their respective radicals in inhibiting tumor growth in LHRH receptor-positive models of human ovarian, mammary, or prostatic cancer. These results suggest that targeted cytotoxic LHRH analogs such as AN-207 could be considered for treatment of these cancers. The presence of receptors for bombesinlike peptides on a wide variety of tumors prompted us to use some of our bombesin/gastrin-releasing peptide antagonists as carrier molecules. Cytotoxic bombesin analogs, such as AN-215 containing AN-201, might find application in the treatment of small cell lung carcinoma (SCLC), and colorectal, gastric, pancreatic, mammary, and prostatic cancers. Since somatostatin receptors are found in various human neoplasms and the receptor subtypes to which octapeptide analogs bind with high affinity have been identified, we synthesized several cytotoxic somatostatin analogs including AN-162 and AN-238 containing DOX and 2-pyrrolino-DOX respectively, linked to octapeptide RC-121. Cytotoxic somatostatin analog AN-238 efficaciously inhibits growth of human breast or prostate cancers expressing somatostatin receptors-2 and -5 and can be used for receptor-targeted chemotherapy. Cytotoxic somatostatin analogs might also find applications for the therapy of human pancreatic, colorectal, and gastric cancer as well as brain tumors and non-SCLC. Cytotoxic compounds linked to analogs of hormonal peptides like LHRH, bombesin, and somatostatin that can be targeted to certain tumors possessing receptors for those peptides could be an important addition to oncological armamentarium.

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Chemotherapy principles in the treatment of prostatic cancer

Cited by 13 publications

References 27 publications

Inhibition of growth of experimental prostate cancer in rats by LH‐RH analogs linked to cytotoxic radicals

Inhibition of growth of experimental prostate cancer in rats by LH‐RH analogs linked to cytotoxic radicals

Combination of long-acting microcapsules of the D-tryptophan-6 analog of luteinizing hormone-releasing hormone with chemotherapy: investigation in the rat prostate cancer model.

Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

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